Cough Responses to Tussive Agents in Health and Disease

The sensitivity of a persons cough reflex can be measured by getting them to breath in (inhale) irritant chemicals. The purpose of this clinical research study is to test the sensitivity of the cough reflex to a variety of chemicals that can be inhaled to see if coughing responses are different between healthy people and people with respiratory problems that make them cough.

Study Overview

• Status: Completed
• Conditions: Asthma; Chronic Cough; Chronic Obstructive Airway Disease
• Intervention / Treatment: Other: Cough Challenge Tests; Other: ambulatory cough recording; Other: Cough questionnaires

Detailed Description

Coughing is a distressing symptom which has a major impact on quality of life. It has been estimated that cough costs the UK economy £1 billion each year. Currently there are no effective anti-tussive agents to treat subjects with cough. Although drugs such as morphine may have some anti-tussive effect, side effects unacceptable.

Currently our understanding of the mechanisms which lead to coughing in different diseases is poor. Many mechanistic studies rely on testing the sensitivity of the cough reflex by inhalation of capsaicin (chilli-pepper extract) or citric acid. These challenges do not differentiate well between health and disease or between different disease states. Other agents such as prostaglandins and bradykinin are known to stimulate a coughing but responses to these agents have rarely been used as a measure of cough reflex sensitivity and not been compared to standard challenges.

It is clear that patients with common airway diseases such as COPD and asthma cough significantly more than healthy subjects. Moreover subjects presenting with chronic cough have cough rates an order of magnitude higher than most patients with airway disease. These differences are poorly represented by the differences in current cough challenge tests.

The investigators hypothesize that patterns of cough responses to different tussive agent may better differentiate between health and different disease states. These patterns may also suggest the different mechanisms leading to cough in different diseases.

• Study Type: Observational
• Enrollment (Actual): 102

Contacts and Locations

Study Locations

• United Kingdom
  • Lancashire
    • Manchester, Lancashire, United Kingdom, M23 9LT
      • University Hospital of South Manchester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adults aged 18 and over who are healthy non smokers, or are current smokers with no respiratory conditions and normal spirometry, or have a diagnosis of asthma, chronic cough or COPD.

Description

Inclusion Criteria:

• General

  • Adult subjects aged 18 years and over

  • Meet criteria for subject groups as outlined below

    (1) Healthy volunteers

  • Non-smokers

  • No history of respiratory disease

    (2) Healthy smokers

  • Current smokers with smoking history of ≥10 pack years

  • Spirometry within normal limits i.e. FEV1>80% predicted and FEV1/FVC ratio >75% predicted

    (3) Asthma

  • Physician diagnosis of asthma
  • Airways hyperresponsiveness to methacholine; PC20<16mg/ml (within last 2 years)

  • Non-smokers or ex-smoker with smoking history of ≤10 pack years

    (4) COPD

  • Physician diagnosis of COPD
  • Ex-smokers with smoking history of ≥20 pack years

  • Spirometry demonstrating airflow obstruction i.e. FEV1/FVC ratio <70%

    (5) Chronic Cough

  • History of a dry cough for >8 weeks
  • Normal CXR
  • Non-smokers or ex-smoker with smoking history of ≤10 pack years

Exclusion Criteria:

• 1) Symptoms of upper respiratory tract infection within the last 6 weeks 2) Participation in another clinical trial of an investigational drug within the last 4 weeks 3) Use of medication likely to alter cough reflex sensitivity i.e. ACE inhibitors, codeine phosphate, morphine sulphate, 4) Patients with severe respiratory disease i.e. FEV1 < 1 litre, 5) Significant medical co-morbidities likely to affect ability to participate in the trial or affect cough reflex sensitivity e.g. diabetes, stroke, Parkinson's disease, multiple sclerosis etc.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Asthma; Subjects with asthma more than 18 years old with minimal or no smoking history and evidence of bronchial hyperreactivity	Other: Cough Challenge Tests; Inhalational cough challenge tests with capsaicin, bradykinin, Citric acid and prostaglandin E2; Other: ambulatory cough recording; Cough recording with a portable device to capture cough sounds; Other: Cough questionnaires; Questionnaires designed to study cough. These include Leicester cough questionnaire, cough visual analogue score and cough quality of life questionnaire.
Chronic obstructive pulmonary disease; Subjects with diagnosis of COPD who must be ex smokers and have evidence of airflow obstruction on breathing tests.	Other: Cough Challenge Tests; Inhalational cough challenge tests with capsaicin, bradykinin, Citric acid and prostaglandin E2; Other: ambulatory cough recording; Cough recording with a portable device to capture cough sounds; Other: Cough questionnaires; Questionnaires designed to study cough. These include Leicester cough questionnaire, cough visual analogue score and cough quality of life questionnaire.
Healthy Volunteers; Healthy non smoking adults.	Other: Cough Challenge Tests; Inhalational cough challenge tests with capsaicin, bradykinin, Citric acid and prostaglandin E2; Other: ambulatory cough recording; Cough recording with a portable device to capture cough sounds; Other: Cough questionnaires; Questionnaires designed to study cough. These include Leicester cough questionnaire, cough visual analogue score and cough quality of life questionnaire.
Healthy smokers; Current smokers with normal breath tests (spirometry)	Other: Cough Challenge Tests; Inhalational cough challenge tests with capsaicin, bradykinin, Citric acid and prostaglandin E2; Other: ambulatory cough recording; Cough recording with a portable device to capture cough sounds; Other: Cough questionnaires; Questionnaires designed to study cough. These include Leicester cough questionnaire, cough visual analogue score and cough quality of life questionnaire.
Chronic cough; Subjects with idiopathic chronic cough.	Other: Cough Challenge Tests; Inhalational cough challenge tests with capsaicin, bradykinin, Citric acid and prostaglandin E2; Other: ambulatory cough recording; Cough recording with a portable device to capture cough sounds; Other: Cough questionnaires; Questionnaires designed to study cough. These include Leicester cough questionnaire, cough visual analogue score and cough quality of life questionnaire.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cough response to tussive agents	To measure cough responses to capsaicin, citric acid, prostaglandin E2 (PGE2) and Bradykinin (BK) in healthy volunteers, airway diseases (asthma and COPD) and chronic cough. To compare the ability of individual challenges and patterns of challenge response to discriminate between diagnostic groups.	45 minutes
Objective cough recording	To perform ambulatory cough recording over 24 hours to assess if there are any differences	24 Hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
C2 to inhaled tussive agents	C2 concentration difference between different diagnostic groups after inhalation of tussive agents	45 minutes

Collaborators and Investigators

• Sponsor: Manchester University NHS Foundation Trust
• Investigators: Principal Investigator: Ashley A Woodcock, FRCP, MD, University Hospital of South Manchester

Publications and helpful links

General Publications

• Belvisi MG, Birrell MA, Khalid S, Wortley MA, Dockry R, Coote J, Holt K, Dubuis E, Kelsall A, Maher SA, Bonvini S, Woodcock A, Smith JA. Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies. Am J Respir Crit Care Med. 2016 Jun 15;193(12):1364-72. doi: 10.1164/rccm.201508-1602OC.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: February 15, 2011
• First Submitted That Met QC Criteria: February 16, 2011
• First Posted (Estimate): February 17, 2011

Study Record Updates

• Last Update Posted (Estimate): September 16, 2011
• Last Update Submitted That Met QC Criteria: September 15, 2011
• Last Verified: September 1, 2011

More Information

Terms related to this study

• Keywords: Cough; Inhalational cough challenges; Cough reflex sensitivity; Chronic cough.
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Signs and Symptoms, Respiratory; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Cough
• Other Study ID Numbers: JAS Protocol 2